Bisphosphonates: The role of chemistry in understanding their biological actions and structure-activity relationships, and new directions for their therapeutic use

Ebetino, Frank H.; Sun, Shuting; Cherian, Philip; Roshandel, Sahar; Neighbors, Jeffrey D.; Hu, Eric; Dunford, J E; Sedghizadeh, Parish P.; McKenna, Charles E.; Srinivasan, Venkat; Boeckman, Robert K.; Russell, R.G.G.

doi:10.1016/j.bone.2021.116289

Cited by 43 publications

(30 citation statements)

References 148 publications

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“…When osteoclasts begin to resorb bone that is rich in bisphosphonate, it is unable to adhere to the bony surface, and to continue bone resorption. Bisphosphonates also promotes osteoclast apoptosis decreasing osteoclast progenitor development and recruitment ( 14 ). For these reasons they are used to treat infants with osteogenesis imperfecta ( 15 ) and results in a decrease in serum calcium.…”

Section: Discussionmentioning

confidence: 99%

Safety and Efficacy of Pamidronate in Neonatal Hypercalcemia Caused by Subcutaneous Fat Necrosis: A Case Report

et al. 2022

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Subcutaneous fat necrosis of the newborn (SCFN) is a panniculitis that develops in fatty areas after fetal or perinatal distress. Prognosis is generally good with complete regression, but it can be complicated by metabolic abnormalities like hypoglycemia, hypertriglyceridemia, thrombocytopenia, and also potentially life-threatening hypercalcemia. Treatments have included hydration, furosemide and corticosteroids. These treatments can be prolonged for several days and can have complications such as nephrocalcinosis. Use of bisphosphonates has been rarely reported in newborn. We describe a case of severe hypercalcemia complicating subcutaneous fat necrosis in a newborn successfully treated by a single dose of pamidronate after having obtained partial response by therapy with hyperhydration, furosemide and hydrocortisone. When high levels of calcium do not respond to first line therapy with hyperhydration and diuretic therapy, bisphosphonates treatment could be considered a valid choice to treat hypercalcemia and to avoid corticosteroids. Further studies are needed to understand if pamidronate and other bisphosphonates can be considered the first choice in hypercalcemia due to SCFN.

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Section: Discussionmentioning

confidence: 99%

Safety and Efficacy of Pamidronate in Neonatal Hypercalcemia Caused by Subcutaneous Fat Necrosis: A Case Report

et al. 2022

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“…A post hoc analysis of the Black study that assessed anti-fracture efficacy in participants having only one infusion of zoledronate or placebo suggested that this was adequate to reduce fracture incidence over 3 years (49). This suggestion of prolonged activity of zoledronate was mirrored in in vitro data documenting its high potency and its very high affinity for bone mineral (50). As a result, Andrew Grey undertook trials to determine the duration of effect of a single infusion of zoledronate 5 mg on BMD and bone turnover, finding residual beneficial effects even a decade later (51).…”

Section: Zoledronatementioning

confidence: 99%

EXTENSIVE EXPERTISE IN ENDOCRINOLOGY: Osteoporosis management

Reid

2022

European Journal of Endocrinology

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Fractures occur in about half of older white women, and almost a third of older white men. However, 80% of the older individuals who have fractures do not meet the bone density definition of osteoporosis, suggesting that this definition is not an appropriate threshold for offering treatment. Fracture risk can be estimated based on clinical risk factors with or without bone density. A combination of calculated risk, fracture history, and bone density is used in treatment decisions. Medications available for reducing fracture risk act either to inhibit bone resorption or to promote bone formation. Romosozumab is unique in that it has both activities. Bisphosphonates are the most widely used interventions because of their efficacy, safety and low cost. Continuous use of oral bisphosphonates for >5 years increases the risk of atypical femoral fractures, so is usually punctuated with drug holidays of 6-24 months. Denosumab is a further potent antiresorptive agent given as six-monthly subcutaneous injections. It is comparable to the bisphosphonates in efficacy and safety but has a rapid offset of effect after discontinuation so must be followed by an alternative drug, usually a bisphosphonate. Teriparatide stimulates both bone formation and resorption, substantially increases spine density and reduces vertebral and non-vertebral fracture rates, though data for hip fractures are scant. Treatment is usually limited to 18-24 months, followed by transition to an anti-resorptive. Romosozumab is given as monthly subcutaneous injections for one year, followed by an anti-resorptive. This sequence prevents more fractures than anti-resorptive therapy alone. Because of cost, anabolic drugs are usually reserved for those at very high fracture risk. 25-hydroxyvitamin D levels should be maintained above 30 nmol/L, using supplements if sunlight exposure is limited. Calcium intake has little effect on bone density and fracture risk but should be maintained above 500 mg/day using dietary sources.

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“…One of the highlighted applications of phosphonates has been reported in the COVID-19 pandemic ( Jockusch et al, 2020 ). Among the various phosphonates and bisphosphonates, hydroxy- and amino-phosphonates and -bisphosphonates are of interest as effective in medicinal and industrial chemistry ( Ebetino et al, 2022 ) ( Santos et al, 2020 ). For example, hydroxy bisphosphonates are well-known bone disease drug candidates, and there are eight clinical hydroxy bisphosphonate drugs that have been introduced for bone diseases due to their high tendency to bind hydroxyapatite, the bone mineral compounds.…”

Section: Introductionmentioning

confidence: 99%

Hydroxy- and Amino-Phosphonates and -Bisphosphonates: Synthetic Methods and Their Biological Applications

et al. 2022

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Phosphonates and bisphosphonates are stable analogs of phosphates and pyrophosphates that are characterized by one and two carbon–phosphorus bonds, respectively. Among the various phosphonates and bisphosphonates, hydroxy and amino substitutes are of interest as effective in medicinal and industrial chemistry. For example, hydroxy bisphosphonates have proven to be effective for the prevention of bone loss, especially in osteoporotic disease. On the other hand, different substitutions on the carbon atom connected to phosphorus have led to the synthesis of many different hydroxy- and amino-phosphonates and -bisphosphonates, each with its distinct physical, chemical, biological, therapeutic, and toxicological characteristics. Dialkyl or aryl esters of phosphonate and bisphosphonate compounds undergo the hydrolysis process readily and gave valuable materials with wide applications in pharmaceutical and agriculture. This review aims to demonstrate the ongoing preparation of various classes of hydroxy- and amino-phosphonates and -bisphosphonates. Furthermore, the current review summarizes and comprehensively describes articles on the biological applications of hydroxyl- and amino-phosphonates and -bisphosphonates from 2015 until today.

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Bisphosphonates: The role of chemistry in understanding their biological actions and structure-activity relationships, and new directions for their therapeutic use

Cited by 43 publications

References 148 publications

Safety and Efficacy of Pamidronate in Neonatal Hypercalcemia Caused by Subcutaneous Fat Necrosis: A Case Report

Safety and Efficacy of Pamidronate in Neonatal Hypercalcemia Caused by Subcutaneous Fat Necrosis: A Case Report

EXTENSIVE EXPERTISE IN ENDOCRINOLOGY: Osteoporosis management

Hydroxy- and Amino-Phosphonates and -Bisphosphonates: Synthetic Methods and Their Biological Applications

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